In recent years, with the continuous improvement of people’s living standards and changes in dietary structure, the number of people suffering from obesity and hyperlipidemia is increasing, and the number of cases of acute pancreatitis caused by hyperlipidemia is also gradually increasing. Hyperlipidemia (HL) is one of the causes of acute pancreatitis (AP), and the resulting pancreatitis is called “hyperlipidemic acute pancreatitis” (HAP). pancreatitis, HAP).
The occurrence of HAP is closely related to serum triglyceride (TG) values, and less related to serum cholesterol values. 1.3% to 3.8% of AP etiology is hyperlipidemia, while 12% to 38% of AP patients have elevated blood TG values. Therefore, HL is both a cause of AP and a common complication of AP metabolic disorders, both of which often form a vicious circle. The clinical features of this type of pancreatitis are somewhat different from the most common biliary pancreatitis and alcoholic pancreatitis, and sometimes it is very easy to misdiagnose. The author combines clinical experience and refers to domestic and international literature to discuss the etiology and pathogenesis, clinical features and diagnosis, treatment options and prevention for the benefit of readers.
1. Etiology and pathogenesis of HAP
There are five main types of HL, with HAP-related types I, IV, and V. Primary HL is common in familial lipid disorders. Primary HL is commonly associated with familial lipoproteinase (LPL) deficiency and familial apo-c II deficiency. The main causes of secondary HL are alcoholism, diabetes mellitus, obesity, hemophagocytosis syndrome, high-fat diet, use of drugs such as triamcinolone acetonide and diuretics, and pregnancy.The pathogenesis of HAP is complex, and HL triggers HAP mainly by affecting pancreatic fluid secretion, inducing pancreatic microcirculatory disorders, and damaging pancreatic alveolar cells by.
(1) HL can put pancreatic blood in a hypercoagulable state, which facilitates thrombosis; together with the aggregation of serum lipid particles blocking the pancreatic microvasculature, thus inducing pancreatic microcirculatory disorders.
(2) HL activates platelets and releases a large amount of thromboxane A2 (TXA2), which has a strong vasoconstrictive effect, while damaging pancreatic vascular endothelial cells and reducing the secretion of prostacyclin (PGI2), which has a strong vasodilating effect, leading to TXA2/PGI2 imbalance and aggravating pancreatic microcirculatory disorders.
(3) Excessive celiac particles embolize in the pancreatic microvasculature or pancreatic parenchyma to form yellow tumors, leading to pancreatic microcirculatory disorders.
(4)In HL, high concentration of TG in the pancreas and peripancreatic is hydrolyzed by pancreatic lipase, which locally produces large amount of free fatty acid (FFA), induces acidosis, activates trypsinogen and aggravates pancreatic self-digestion.
(5) FFA produces direct cytotoxic effects on pancreatic alveolar cells and capillary endothelial cells, and causes biofilm damage and increased permeability by enhancing the toxic effects of cytokines such as tumor necrosis factor, leading to mitochondrial swelling and deformation, and aggravating the continuous ischemia and necrosis of the pancreas.
2. Clinical features and diagnosis of HAP
HAP is similar to other causes of pancreatitis in terms of clinical manifestations, mainly manifesting as persistent epigastric pain that can radiate to the lower back, abdominal distension, nausea and vomiting. However, there are differences in the medical history of hyperlipidemic pancreatitis patients may have a tendency to alcoholism, obesity, pregnancy, diabetes mellitus, and in a small percentage of patients, a family or personal history of hypertriglyceridemia. Hyperlipidemic pancreatitis has an acute onset, and patients with HAP have mild clinical symptoms, manifesting as a transient elevation of amylase, with few complications, mostly mild AP, but with a tendency to recurrent episodes.
Patients with AP with HL have more severe clinical symptoms, often accompanied by severe metabolic disorders in the body (such as rapid increase in blood glucose, multi-organ insufficiency syndrome, etc.), with many complications and poor prognosis. When the blood TG value is extremely elevated, patients with HAP will have severe abdominal pain, inducing fulminant AP or even death; and the incidence of HAP combined with pancreatic abscess, fatty liver and low-density lipoproteinemia is also correspondingly higher.
In HAP, there is a non-lipid inhibitory factor in the plasma that inhibits blood amylase activity, which can enter the urine through the kidney and inhibit urinary amylase activity. Therefore, blood and urine amylase activities are often not significantly elevated in patients with HAP. The disease should be highly suspected in the presence of severe abdominal pain during pregnancy, when other etiologies are excluded. For those who have clinical suspicion of HAP, but no or insignificant elevation of blood and urine amylase, the diagnosis can be further assisted by ultrasound, CT or MRI to understand the pancreatic and peripancreatic conditions, especially dynamic enhanced CT, which has a greater reference value for the presence or absence of pancreatic necrosis.
Once pancreatitis is established, TG > 11.3 mmol/L or TG 5.65-11.3 mmol/L and celiac disease in the serum, excluding other causes of pancreatitis can be diagnosed as hyperlipidemic pancreatitis (HAP), for those whose blood lipids are higher than the reference range, but the serum is not celiac It can only be called pancreatitis with hyperlipidemia or a transient increase in blood lipids due to stress of pancreatitis.
3.Treatment and prevention of HAP
HAP exhibits both the general characteristics of AP and its specificity. Although there is no uniform and effective treatment plan for HAP, the key to the treatment of HAP is to rapidly remove the primary and secondary factors causing HL and reduce the blood TG value based on the standardized treatment of AP. When the blood TG value is reduced to below 5.65 mmol/L, the further development of HAP can be stopped.
3.1 Conventional treatment for pancreatitis: conventional treatment includes fasting, gastrointestinal decompression, nutritional support, inhibition of pancreatic exocrine secretion, inhibition of pancreatic enzyme activity, prophylactic antibiotics, and maintenance of water-electrolyte acid-base balance. It should be noted that fat emulsion should be regarded as contraindicated for parenteral nutrition support in these patients, especially when TG>4.5 mmol/L, which will increase the amount of blood lipids in the body and aggravate the disease.
At present, there is a standard for the use of fat emulsion, namely: TG1.7-3.4mmol/L can be used, 3.5-4.5mmol/L should be used with caution, and the body lipid level should be tested regularly during the application process. For patients with severe HAP, long fasting time and poor general condition of patients in the later stage, if the blood TG value is between 1.7 and 3.4 mmol/L, under the condition of strict monitoring of blood lipids, short and medium chain fat emulsions ≤ 750 mL and long chain fat emulsions ≤ 250 mL can be administered for 24 h. If the blood TG value is > 5.65 mmol/L after 1 or 2 h of fat emulsion input, the patient should immediately stop. mmol/L, it should be stopped immediately. During the use of fat emulsion, the fat profile test should be reviewed regularly, and those with positive test should also be discontinued in time.
3.2 Application of lipid-lowering drugs: Lipid-lowering drugs can be given through nasal feeding tube or enteral nutrition tube. Lipid-lowering drugs can effectively reduce the blood TG level by 20% to 60%. For primary HAP, beta-lipid-lowering drugs such as fenofibrate, gemfibrozil and benzofibrate are preferred. The lipid-lowering mechanism is to enhance lipoproteinase activity and promote TG hydrolysis, and some data say that beta-lipid-lowering drugs can reduce 50% of TG level and increase 20% of HDL cholesterol level at the same time.
Jain et al. showed that long-term administration of fenofibrate could maintain normal serum TG levels and effectively prevent the recurrence of pancreatitis. Niacin has a significant effect on raising HDL and can lower serum TG levels by 30%-50% by inhibiting the synthesis of very low density lipoproteins, so its efficiency in lowering TG is lower than that of fibrates. Statins are not preferred for hyperlipidemia, which is mainly cholesterol elevation. Because of the slow onset of oral lipid-lowering drugs, patients often have abdominal distension during the onset and should not eat, so they are mostly recommended for prophylactic use.
3.3 Hemopurification: Hemopurification, including plasma exchange and hemofiltration, can be considered for patients with severe HAP. Plasma exchange (PE) means that the patient’s blood is drawn in fractions, the plasma is removed to exclude the contained TG and excessive inflammatory cytokines, the other components of the blood are returned to the patient, and fresh frozen plasma and albumin are reintroduced. A few cases abroad have reported significant recent improvement and a significant reduction in relapse rates in patients treated with PE.
Kyriakidis et al. treated 5 patients with HAP with plasma exchange and found that it was effective in reducing lipid levels and improving symptoms. Except for one case that underwent surgery, no one died of disease and all had no recurrence at 4-28 months of follow-up. The timing of PE is the key to successful treatment and should be performed as soon as possible after the onset of the disease, mostly within 48-72 h.
The best time for HF treatment is within 72 h after the onset of the disease, and the earlier the effect, the more obvious it is. During this period, it is absolutely forbidden to administer any fat emulsion to avoid further increase of TG.
3.4 Application of heparin and insulin: Lipoproteinase (LPL) is a key enzyme of endogenous and exogenous lipid metabolism and plays an important role in the clearance of blood lipids. Continuous intravenous infusion of heparin (or subcutaneous injection of low-molecular heparin) and insulin (blood glucose control below 11.1 mmol/L) can activate LPL, accelerate celiac degradation, significantly reduce blood TG value, improve pancreatic microcirculation, and prevent neutrophil activation, which is an effective treatment for HAP. berger et al. treated 5 patients with severe HAP with continuous intravenous push of low-molecular heparin and insulin, and all patients’ blood TG values decreased to below 2.8 mmol/L, and no one case had complications or died of disease.
3.5 Traditional Chinese medicine: Traditional Chinese medicine recognizes HAP as solid heat or heat entrapment, internal Qi obstruction, and solid heat in the spleen and stomach. Therefore, the basic principle of treating this disease is to pass through the lining and attack, clear heat and detoxify, and activate blood circulation and remove blood stasis. In order to maintain effective blood volume, prevent shock, and reduce inflammatory response, Shengwan injection and Huangqi injection, which benefit qi and save yang, are commonly used, together with low-molecular dextrose or corticosteroid drugs. In order to release intestinal paralysis and enhance intestinal peristalsis and control the translocation of intestinal bacteria, the method of Tongli tapping is often used, and the formula is Da Cheng Qi Tang, Huang Lian Detoxification Tang plus or minus, Gentian Diarrhea Liver Tang plus or minus, and also the method of external application of Pi Nu whole abdomen or raw rhubarb gavage can be used to assist the absorption of ascites, exhaust and defecate, reduce intra-abdominal pressure and improve symptoms.
3.6 Surgical intervention: Surgical intervention should avoid the acute reaction period, but if combined with abdominal compartment syndrome, intra-abdominal pressure is not relieved by short-term conservative treatment, open decompression and drainage should be implemented. As for the timing of surgical intervention, the current consensus is that pancreatic necrosis with infection is an absolute indication for surgery, and the main purpose of surgery is to remove necrotic tissue and lavage and drainage of the abdominal cavity to stop the progression of the disease.
For patients with no peripancreatic infection but large amount of peritoneal fluid, peritoneal tube drainage and lavage can be used to transfer peritoneal exudate rich in pancreatic enzymes and a variety of harmful substances out of the body, diluting the concentration of enzymatic toxins in peritoneal exudate and reducing the local and systemic damage caused by it.
4.Prevention of HAP
4.1 General prevention: control diet, take lipid-lowering drugs to reduce blood lipid levels, and obese people should increase exercise and reduce body weight. Obesity is an independent risk factor of AP, and is also an important indicator to judge the prognosis of AP, and has a strong correlation with HL.
4.2 Prevention in specific populations: Pregnant women should monitor lipids and lipoproteins throughout pregnancy, and once elevated lipids are detected, lipids should be controlled by diet and lipid-lowering drugs should not be taken. Glueck et al. concluded that for estrogen or triamcinolone, blood TG >7.90 mmol/L should be discontinued and blood TG >3.39 mmol/L is a relative contraindication to the use of drugs. Other drugs such as diuretics and β-blockers, if abnormalities occur during application, dietary modifications can be made first, and should be discontinued if they are ineffective.
4.3 Gene therapy: For hyper-TGemia caused by hereditary LPL deficiency, some foreign scholars have proposed the application of gene therapy. This method is still in the research stage. Animal experiments have shown that after the injection of a drug called AAV1-LPLS447X into LPL-deficient felines and mice, myogenic cells can produce and secrete enzymatically active LPL, which can reduce blood TG level by 97% and maintain it for more than 1 year.
5. Outlook
With the improvement of living conditions, the incidence of HAP is increasing year by year. Clinicians should pay great attention to this, and lipid measurement should be included as one of the routine tests for admission to AP, so as to facilitate early diagnosis and timely treatment. It is reasonable to believe that the prognosis of HAP patients will be further improved as medical workers and researchers pay more attention to HAP and research on the correlation between HL and AP is intensified.